Pain is generally divided into nociceptive and neuropathic pain. Nociceptive pain stems from neural pathways in response to tissue damaging or potentially tissue damaging signals, and includes inflammatory pain. Neuropathic pain tends to relate to dysfunctions within the nervous system. Unfortunately, agents that treat one kind, of pain do not necessarily treat the other. Anti-inflammatory agents, for example, do not relieve the “phantom limb” pain felt by amputees.
In mammals, inflammatory pain is driven primarily by arachidonic acid (sometimes abbreviated, as “AA”). Inflammatory pain develops as a result of tissue injury such as a cut or a bacterial infection upon which a large amount of AA is released at the site of inure by the actions of phospholipases. Synchronized to this event is the upregulation of cyclooxygenase-2 (COX-2), an enzyme which converts the released AA to prostaglandins, potent pain producing molecules. Released AA is metabolized by cyclooxygenases (“COX”), lipoxygenases (“LOX”) and cytochrome P450 epoxygenases to yield prostaglandins, leukotrienes and epoxy-eicosatrienoic acids (“EETs”) respectively. These materials may be further metabolized, for example they may be converted to bioactive amides and conjugates. Inflammatory pain is well correlated with the production of Cox-2 metabolites of AA, the prostaglandin series molecules. Consequently, a profound decrease in pain follows the inhibition of the inducible Cox-2, which is often attributed to the reduction of PGE2, a key regulator.
In contrast, in neuropathic pain, there is little evidence am inflammatory process mediated by arachidonic acid, cyclooxegenases and prostaglandins. Neuropathic pain is caused by a lesion of the peripheral or central nervous system (or both) manifesting with sensory symptoms and signs. Underlying causes include infections, trauma, metabolic abnormalities, chemotherapy, surgery, irradiation, neurotoxins, inherited neurodegeneration, nerve compression and tumor infiltration. Mechanisms of neuropathic pain are described, for example, in Zhuo. Molecular Pain (2007) 3:14 Campbell and Meyer, Neuron (2006) 52(1):77-91 Dworkin, et al., Arch Neurol (2.003) 60:1524-34.
The pharmacological agents that have most commonly been shown to effectively block neuropathic pain are tricyclic anti-depressants (TCAs). However these agents are not effective at all in some patients and are only partially effective in others. Therefore the therapy of neuropathic pain is an unmet and growing clinical need. TCAs have many disadvantages well known in the field. Since neuropathic pain is a debilitating and hard to treat condition, however. TCAs have been used despite their disadvantages in the absence of agents with less adverse effects.